How to Treat PTSD-Related Sleep Disturbances?

Today’s question is: How to treat sleep disturbances in patients with PTSD?

Here is a summary of this episode:

Prazosin is recommended as a first-line agent in sleep disturbances in PTSD with an average dose for men at 16 mg and for women, 7 mg titrated over 5 weeks.

Trazodone can be used in patients with initial-sleep insomnia with PTSD at a starting dose of 50 mg.

Avoid benzodiazepines due to its abuse potential. Also, its cognitive side effects may negatively affect psychotherapy effectiveness.

Quetiapine should not be used first-line in the treatment of insomnia. It is associated with weight gain, which is not dose-related.

Transcript

Hello everyone and welcome to the Psychopharmacology Institute podcast. I’m your host, Dr. Wegdan Rashad. In this series we will be discussing topics that matter to you, the mental health clinician, in your practice, sharing expert opinions and the latest research.

Today we will be talking about pharmacotherapy of post-traumatic stress disorder, aka PTSD. We will take a particular focus on the treatment of sleep disturbances. We will do this with the help of snippets from Dr. David Osser’s lecture on PTSD algorithms available on our website. Dr. Osser is an Associate Professor of Psychiatry at Harvard Medical School. He is also the founder of the psychopharmacology algorithm project, a useful resource that I have personally used during my residency training. Details on the project will be covered later.

Now, before alarm bells start ringing in your head when we begin talking about medications in PTSD, I want to make it clear that PTSD, as we know, is associated with both psychological and biological disturbances. There are effective and approved psychosocial treatments for it. Our focus is for the clinician that chooses to use psychotropics, but that does not by any means undermine the importance of psychosocial interventions.

According to the DSM 5, there are 4 main symptom clusters of PTSD; one, avoidance symptoms, two, re-experiencing (like nightmares and flashbacks), three, negative changes in mood and cognition and four, arousal symptoms (like hypervigilance and insomnia for example). OK, now that’s out of the way get ready for some statistics.

Did you know that up to 90% of PTSD patients experience insomnia? Did you also know that up to 70% experience more than 5 nightmares per week? THAT is pretty devastating and you could pretty much be that patient’s hero if you can prescribe correctly to reduce or rid them of nightmares altogether. Also, treating PTSD sleep symptoms can improve daytime core symptoms.

Great! Dr. Osser will now explain the mechanism by which sleep symptoms arise.

Dr. Osser:
Regarding pathophysiology, a word about the pathophysiology of the sleep problems, because that’s going to help you understand our recommendations for treating it. There seems to an increased noradrenergic activity during sleep in patients with PTSD. While trying to fall asleep, this might be what is also making things difficult. The adrenaline is just flowing, it’s a fight or flight feeling much like they had when they were exposed to the original traumas. So it would be good if we have medication that could reduce noradrenergic activity in the brain, but the main treatments usually recommended for PTSD, indeed the only FDA approved treatment, SSRIs, actually exacerbate these symptoms and can make sleep worse. But there is a class of drugs, one of which is prazosin, that are adrenergic blockers, and they target the impaired sleep in PTSD patients. And as it does so, it also produces substantially larger effect sizes in improvement in other symptoms of PTSD even during the day.

And this is where we start our interesting relationship with prazosin. So, because of prazosin’s alpha-adrenergic blocking abilities, it theoretically can improve sleep. Take note that prazosin is not a sedating agent in itself.

Dr. Osser:
After you’ve ruled out or managing other causes of sleep disturbances, and if the patient has PTSD-related nightmares or disturbed arousals, we recommend you consider a trial of prazosin as the first-line medication treatment.

What is the evidence behind this?

Dr. Osser:
To discuss the efficacy issues with prazosin, we’re at a critical point in this lecture today because this evidence is somewhat mixed as I am about to share with you. There are five placebo-controlled randomized trials with prazosin. They’re all from Dr. Raskind’s group in Washington, affiliated with the University of Washington. The four published studies were all very positive. The impact on PTSD symptoms was mostly twice as great with the drug as on placebo which can be translated to an effect size of 1 or 1.0. If you look just at the effect on nightmares though, it was a 200% increase over placebo for the effect size on nightmares. That would translate to a 2.0 effect size. Now to put into contrast, what do you think the effect size of SSRIs are on PTSD symptoms? In a 2015 meta-analysis of all the SSRI studies in PTSD, the effect size was 0.23. That was the mean effect size of all the SSRIs. That’s only 23% better than placebo.

The effect size of prazosin is really quite impressive. But it’s not all fun and games with prazosin, first in terms of its side-effect profile and second because of the looming, dark shadow that the 5th study has cast upon us. Enough suspense? Not quite! Let’s review the side effect profile first!

You may already know this but prazosin was classically used to treat hypertension. So one of its prominent side effects in causing hypotension. Hypotension in the elderly can cause an increased likelihood of falls and fractures. This can be of particular concern in patients who are already on antihypertensives. Dr. Dana Wang asks Dr. Osser about monitoring.

Dr. Wang:
How do you monitor the BP when starting prazosin? I have asked my patients to buy the BP cuff and monitor daily in the beginning before the dosage is stabilized, is this necessary?

Dr. Osser:
I do not do that. I don’t monitor blood pressure routinely. I only do it if they develop possible dizziness or other signs that might suggest they’re having blood pressure problems. And sometimes, it can be unclear whether this is a blood pressure related symptom or whether it’s another kind of problem like sedation. So the blood pressure is useful there. So I guess it would be good for them to have a blood pressure cuff handy if they’re doing this at home so that they could check it and help determine the cause of any symptoms they’re having.

Be sure to check the full interview which will be released soon on our website for all our listeners. So, watch this space.

Now, the results of this 5th trial came out in February 2018 by Dr. Raskind and his team. It was conducted on nearly 300 military veterans with chronic PTSD. Half were given prazosin and half were given placebo, titrated over 5 weeks. The results revealed that prazosin did not alleviate distressing dreams OR improve sleep quality compared to placebo. Quite a disappointing result. I emailed Dr. Osser about this study and he wrote, “But it [this result] doesn’t negate the results of the other positive placebo-controlled studies plus numerous observational studies and recorded clinical experiences with prazosin which is positive – very positive.”

According to a commentary by Dr. Peter Roy-Byrne, he said, quote, “These findings may have been negative because participants were relatively stable, nonsuicidal veterans without substance dependence who were not deemed ill enough by their treating clinicians to treat openly with prazosin… Also, participants were not screened for sleep apnea, which could have interfered with prazosin’s effects.”

He also went on to propose that perhaps this group of patients had a subtype of PTSD that was less adrenergically driven. The rest of the commentary is referenced in the transcript of this podcast. And despite this latest evidence, Dr. Osser’s algorithm still recommends using prazosin as a first-line treatment for PTSD-related sleep disturbances.

Now let us speak a bit about the dosing of prazosin.

Dr. Osser:
A couple of studies have been published showing that 85% to 90% of patients who are put on prazosin are given a subtherapeutic dose and the clinicians give out prematurely. The reason seems to be just lack of knowledge of what the protocol was that Raskind used in his four studies for dosing the patients. I’m gonna share that with you right now. But there is also another barrier besides knowing the protocol and that is that this protocol takes some time to administer.

OK, we’re ready.

Dr. Osser:
So, here’s how it was. First of all, there’s two different protocols for the men and the women. We don’t know why but for men, you seem to need significantly more to get the same effect. So first of all, where are you going? You’re going for a mean average dose at endpoint of 15.6 or about 16 mg. That was the average of Raskind’s fourth and final published study in 2013. That meant that half of the veterans needed more and half needed less than 16. And how did he get there? He went with 1 mg at bedtime for two nights, then 2 mg for five nights. Then, 4 for seven nights, 6 for seven nights, 10 for seven nights, 15 for seven nights. So in other words, it took five weeks to get to the average dose and then 25 after seven nights on 15. That’s the maximum he used in that study.

Now, the protocol for women is roughly half of that at the end, although it starts the same. Ten was the maximum that they used in that study. The median dose that was effective was 7.

So the average dose for men is about 16 mg and for women 7 mg, titrated over a period of 5 weeks. Also, patients were given a mid-morning dose for daytime symptoms. The mean mid-morning dose was 4 mg for men and 2 mg for women in that protocol.

Dr. Osser:
The goal of treatment is to eliminate these disturbed awakenings and give them a smooth night of sleep. And that’s one of the reasons people stop at earlier doses. Maybe they’ve been having a nightmare every night, maybe two or three times a night for years. And now after they get up to 4 or 6 of prazosin, it’s down to only two or three nightmares a week. Wow, the patient is very happy. And the doctor may be happy too, but not realizing that if they keep going, the nightmares could be eliminated altogether.

So, aim for complete remission of nightmares.

Now, to recap, we have touched upon how sleep disturbances may arise in PTSD, and how that relates to prazosin. We have also reviewed the efficacy studies and side effects of prazosin as well as the dosing for both men and women. Now let’s briefly see what alternatives we have.

What if your patient still has disturbed sleep, particularly in initiating sleep? Well, according to the algorithm the next step you could do is to introduce our good old friend, trazodone.

Dr. Osser:
Our first-choice hypnotic for helping them fall asleep is trazodone. I’m sure you’re familiar with trazodone. It’s a sedating antidepressant. It’s shown some effectiveness for sleep disturbances in PTSD, but really only in open-label studies. It has been described, though, as an ideal hypnotic agent by Stephen Stahl in an article he wrote a few years ago because of its triple sleep-promoting actions on the 5-HT2A, alpha one, and H1 receptors. It also has a short half-life, no weight gain, low risk of dependence, no problems with sexual side effects, so it’s got a lot of things that make it a relatively ideal choice for many patients.

Any evidence supporting its use in PTSD?

Dr. Osser:
Now, as far as what evidence we do have with trazodone, there is that one open-label study. What I do offer, though, is two studies of using trazodone versus placebo for SSRI-induced insomnia. SSRIs, as noted, often cause insomnia as a side effect, maybe 15 or 20% of patients, and in two randomized controlled trials, trazodone was an excellent treatment for that. It also has been compared with zolpidem for primary insomnia. It was in a large trial which also had a placebo control, and it proved comparable in efficacy for primary insomnia. So, there’s a variety of lines of evidence that trazodone is a reasonable insomnia treatment that you might apply in this situation.

The ideal starting dose is 50 mg. If the patient finds it too sedating you can halve the dose to 25 mg or even 12.5 mg at night. When I prescribe trazodone, I let my male patients know about one of its rare, but rather disturbing side effects, which is… you guessed it, priapism.

Dr. Osser:
The side effects of trazodone include excess sedation, dizziness, orthostatic problems occur from time to time, and syncope occasionally. So, you do have to be cautious for worrying about and watch for that. Now, perhaps the most often-mentioned side effect, though, in males is priapism, and that is a concern. It’s an infrequent concern. Serious priapism only occurs in one in 2000 or 3000 patients, but you do need to warn people about it, and in theory the risk of priapism may be increased if you combine trazodone with prazosin, which has a very rare, sometimes not even mentioned in typical patient information sheets that prazosin has been associated with priapism. So, some have thought that you shouldn’t combine prazosin with trazodone, because of a possible increased risk of priapism. So far, there hasn’t been any reported cases of priapism in this commonly-used combination. Nevertheless, extra caution with warning about priapism is certainly necessary in combining them, and we do that routinely.

We are nearing the end of this review of the treatment of sleep symptoms in PTSD. Before I go, there are a couple of important things for you to know; one about benzodiazepines and the other about prescribing quetiapine for sleep.

Dr. Osser:
Now, what about benzodiazepines? Benzodiazepines have high potential for abuse in patients with PTSD. A big study showed that; more than other anxiety disorders, and this is with or without comorbid substance use disorder in those patients. So certainly if the patient has a history of substance abuse you certainly would want to avoid them. But if you, for some reason, did prescribe, be sure it would be a small quantity to test their ability to use it appropriately. They could be considered if there’s a past history of clear response without significant abuse or misuse. You should know, though, that in the few studies, benzos have no efficacy for the primary symptoms of PTSD. Another problem is that they may reduce the short or longterm effectiveness of psychotherapies for PTSD, such as exposure therapy. That’s another significant concern: if you can’t remember the therapy, then it’s not going to do that much good. At least that’s what seems to be the mechanism proposed in these studies.

And that leaves us, finally, with quetiapine which is widely prescribed for sleep in PTSD. It deserves a lot more time than I have today to tell you why you shouldn’t be doing it, but I will refer you to a review article on reports of using quetiapine for sleep in various patient populations that concluded that, quote: The benefits did not justify the risks. And it should not be used as a first-line treatment for any kind of insomnia. It’s interesting to note that the weight gain from quetiapine is not dose-related. Unlike other antipsychotics like olanzapine, where the weight gain is dose-related, it is not with quetiapine. So you can get the Seroquel munchies is what some of my veterans refer to it, this running into the kitchen about a half hour after you take it and having a couple of peanut butter and jelly sandwiches. Night after night, so they can gain a lot of weight on 25 or 50 milligrams for sleep and this definitely is not a great thing for these patients.

So it would be better to avoid benzos and watch out for those Seroquel munchies!

Be sure to check out Dr. Osser’s algorithms at psychopharm.mobi and the full lecture on our website.
And congratulations for getting this far.

Now, for the key points!

Key Points

Sleep disturbances in PTSD may be due to increased noradrenergic activity during sleep.

Prazosin is an alpha-adrenergic blocker which explains why it can improve sleep symptoms.

Prazosin is recommended as a first-line agent in sleep disturbances in PTSD with an average dose for men at 16 mg and for women, 7 mg titrated over 5 weeks. The mean mid-morning dose is 4 mg for men and 2 mg for women.

Prazosin can cause hypotension but generally does not require routine monitoring. It is also theoretically associated with an increased risk of priapism when used with trazodone.

Trazodone can be used in patients with initial-sleep insomnia with PTSD at a starting dose of 50 mg.

Avoid benzodiazepines due to its abuse potential. Also, its cognitive side effects may negatively affect psychotherapy effectiveness.

Quetiapine should not be used first-line in the treatment of insomnia. It is associated with weight gain that is not dose-related.

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The following people participated in this episode: Dr. Flavio Guzman as the general editor, Mark Young as the audio engineer, Pamela Gonzalez as the project manager and myself, Dr. Wegdan Rashad as the host. We’d also like to thank Dr. David Osser, and Dr. Dana Wang, for being with us.

Thank you for joining us in today’s podcast until the next episode, goodbye!